The present invention relates to new products that may be implanted into cells or a target tissue. The invention also relates to components and devices that may be used in the delivery of said products to cells and tissues. In a further aspect, the invention relates to methods of fabricating said products, components, and devices. In a yet further aspect the invention relates to a new particulate product.
It is known that gold particles coated with DNA may be used to transfer DNA into cells. This is achieved by accelerating the particles towards a target of cells. The particles then pass through the cell walls and/or membranes carrying the DNA into the cell. Compressed gas such as helium is commonly used to bring about this acceleration.
A similar technique has also been developed to inject particles through the skin of a patient. Again the particles are accelerated by compressed gas and pass through the skin into the body of the patient. The particles can be used to inject drugs, DNA, or vaccines to the blood stream or tissues of humans or animals.
The implantation of particles into tissue or cells in this way is known as microprojectile implantation, and involves acceleration of a particle to a velocity that allows it to penetrate a cell wall and/or membrane or to penetrate tissue. Microprojectile implantation differs from other forms of implantation since it is the momentum of the particle that causes the breach in the cell wall or tissue, as opposed to an implement such as a needle or surgeon's knife. A further factor that affects implantation depth and degree of tissue damage is the shape of the microprojectile particle.
Microprojectile implantation has several advantages over other forms of implantation. The technique makes it easier for human patients to self administer an active substance, eliminating the use of needles. The active substance can be used in dry form, potentially increasing stability of many active substances. The procedure is significantly less painful than needle delivery and is hence particularly favoured for paediatric use. Finally since the active substance can be delivered in particulate form the release of the substance may, in certain circumstances, be better controlled.
A microprojectile is a particle having a composition, size, shape, and mass such that it is suitable for microprojectile implanation into a target tissue or cell, or into the blood stream of a patient. If the microprojectile is being administered to tissue (eg skin), the velocity and momentum must be set to achieve the correct level of penetration in order to achieve the desired physiological effect. Microprojectiles are typically used in association with an active substance, such as a drug or biological material. The properties that make the particle suitable for microprojectile implantation will depend upon the active substance to be delivered to the target, upon the technique used to deliver the particles, and upon the target tissue or cell. For example if a microprojectile is to be introduced into a cell, then its constitution and velocity must allow it to penetrate the cell wall and/or cell membranes without destroying the cell. Typically the particle must be approximately one tenth the size of the cell to be implanted. If, on the other hand, it is for extracellular drug delivery, its size is significantly larger, and often in the 10 to 100 micron range.
The active substance may be coated onto the microprojectile, for example DNA may be precipitated onto the surface of gold particles. In the case of a drug to be implanted in a patient, the microprojectile may simply consist of an excipient combined with the drug. A relatively low density material such as ice may be used as a carrier material for the active substance: the substance may be dissolved or otherwise combined with water; the solution/suspension is then nebulised and the resulting droplets frozen. The frozen droplets can then be implanted into the cells where the ice melts releasing the substance.
A number of devices may be used to deliver microprojectiles to the target cells or tissue. Such devices (delivery devices) typically comprise a gas source and a component (a carrier component) for retaining the microprojectiles prior to delivery. The gas source is often a small pressurised helium cylinder and can be activated by puncturing the cylinder to release a flow of helium. The device, often termed a gene gun if the material to be delivered is genetic, may be arranged so that the flow of helium causes the microprojectiles to be accelerated towards the target. For example the carrier component may comprise a disc upon which the microprojectiles are adhered, the flow of gas causing them to be dislodged from the disc. The carrier component and gas source are usually designed to facilitate their replacement so that the microprojectile delivery device may be used many times.
It is known that products may be implanted in human or animal patients by techniques other than microprojectile implantation. For example an implant may be introduced surgically or by injection though a needle. Both these techniques are referred to in PCT/GB99/01185, which describes the use of porous and polycrystalline silicon implants. There are several types of porous and polycrystalline silicon including: biocompatible silicon, bioactive silicon, and resorbable silicon. The fabrication and properties of these three types of silicon are referred to in PCT/GB96/01863.
There are a number of problems associated with existing microprojectiles. Many microprojectiles currently used are only able to carry a small amount of active substance in relation to their size. Prior art microprojectiles are typically solid, so that the active substance is confined to the surface of the microprojectile. The surface location of the active substance means that it is exposed to forces during passage of the microprojectile into the target, and is therefore vulnerable to damage. Where the active substance comprises large organic molecules such as DNA, then passage of the microprojectiles through the skin of a patient may cause the DNA molecules to fragment. The immune response of a patient may also cause deactivation of the substance as a result of its surface location.
Prior art microprojectiles, which have sufficient mechanical strength to withstand the forces of implantation, are typically fabricated from materials that are insoluble in biological environments. This can hinder the release of the active substance into the cell or tissue. For example DNA present on the surface of gold particles is immobilised by the gold, hindering transfection of the DNA. This immobilisation means that the DNA may be degraded before it can be intercalated into the nucleus of the implanted cell. Though in some cases it may be advantageous for the DNA to remain on the gold in an active form. Another material commonly used in the fabrication of microprojectiles is tungsten. Tungsten is inexpensive relative to gold, but it suffers from several disadvantages. It is difficult to fabricate tungsten microprojectiles having as uniform size distribution. Tungsten is also potentially toxic; and finally is also known to catalytically degrade DNA bound to its surface.
The factors that affect whether a material is suitable for use in microprojectile implantation are therefore complex. Properties such as density, toxicity, mechanical strength, internal structure, surface properties, and solubility in a variety of environments, may all affect the performance of the material.